How to manage numbness and tingling in amyloidosis?

Management of Numbness and Tingling in Amyloidosis

For ATTRv amyloidosis with polyneuropathy, initiate TTR silencer therapy immediately (patisiran, vutrisiran, or inotersen) as these are FDA-approved disease-modifying treatments that can stabilize or reverse neuropathy progression, while simultaneously managing symptoms with pregabalin, gabapentin, duloxetine, or tricyclic antidepressants. 1

Disease-Directed Therapy: The Priority

TTR Silencers for ATTRv Polyneuropathy

• Three FDA-approved TTR silencers are available: patisiran and vutrisiran (small interfering RNAs) and inotersen (antisense oligonucleotide) 1
• These medications block RNA translation to prevent transthyretin protein synthesis 1
• Early treatment is critical: patients treated earlier have significantly better neuropathy outcomes and quality of life compared to those whose treatment is delayed by 1 year or more 1
• In pivotal trials, these agents achieved stabilization or reversal of disease progression relative to pretreatment baseline 1
• Mandatory vitamin A supplementation: all patients require 3,000 IU daily vitamin A because transthyretin normally transports retinol 1
• Patisiran requires premedication with corticosteroids to prevent infusion-related reactions 1

Important Limitation

• Tafamidis is NOT FDA-approved for neuropathy (only approved for cardiomyopathy), though it is approved in Europe for polyneuropathy 1, 2

Symptom Management: Concurrent with Disease-Directed Therapy

Sensory Neuropathy (Numbness, Tingling, Pain)

• First-line agents: pregabalin, gabapentin, duloxetine, or tricyclic antidepressants 1, 3
• Start with low doses and titrate based on efficacy and tolerability 3
• These medications address the neuropathic pain, burning, and paresthesias that characterize small-fiber involvement 1, 3

Autonomic Dysfunction Management

• Orthostatic hypotension: increased salt/fluid intake, salt tablets, fludrocortisone, midodrine, or droxidopa 1
• Gastrointestinal symptoms: manage alternating diarrhea/constipation and night diarrhea symptomatically 1
• Urinary retention and erectile dysfunction: address as clinically indicated 1

Critical Diagnostic Distinctions

Rule Out Mimics Before Attributing to Polyneuropathy

Carpal tunnel syndrome often precedes polyneuropathy by many years in amyloidosis and causes similar numbness/tingling in the hands 1

• Affects lateral palm and fingers specifically 4
• May require separate surgical intervention

Lumbar stenosis/lumbosacral radiculopathy can mimic polyneuropathy but has opposite symptom patterns 1:

• Neurogenic claudication: numbness/pain/weakness after walking short distances
• Persists with standing but relieved by sitting or lying down
• This is the opposite of polyneuropathy symptoms, which worsen when lying in bed and improve with walking 1

Confirmatory Testing

• Electromyography and nerve conduction studies for large-fiber involvement 1
• Skin biopsy for epidermal nerve fiber density when small-fiber neuropathy is suspected, as conventional nerve conduction studies will not detect it 1
• Sweat gland nerve fiber density with amyloid staining (optional) 1

Clinical Monitoring

Functional Assessment

• Use the Familial Amyloid Polyneuropathy (FAP) staging in clinical practice 1:
  • Stage 1: walks unassisted
  • Stage 2: walks with assistance (cane or walker)
  • Stage 3: wheelchair- or bed-bound
• This provides practical tracking of disease progression 1

Physical Examination Findings

• Distal sensory loss (begins in toes/feet, progresses to fingertips) 1
• Reduced or absent reflexes 1
• Distal muscle weakness (toe extensors, then ankle dorsiflexors) 1
• Wide-based unsteady gait from proprioceptive loss 1

Common Pitfalls to Avoid

Delaying TTR silencer therapy: the window for optimal benefit narrows with disease progression, as amyloid neuropathy progresses 15-20 times more rapidly than diabetic neuropathy 1

Forgetting vitamin A supplementation: this is mandatory with all TTR silencers and easily overlooked 1

Misattributing all symptoms to polyneuropathy: carpal tunnel syndrome and lumbar stenosis are distinct entities requiring different management despite causing similar numbness patterns 1

Using conventional nerve conduction studies alone: these miss small-fiber neuropathy, which is often the initial presentation 1

Type-Specific Considerations

AL Amyloidosis

• Polyneuropathy occurs in 17-35% of patients 1
• Prognosis is generally worse than ATTRv, with median survival of 25 months when neuropathy is dominant 5
• No specific FDA-approved neuropathy treatments; focus on treating underlying plasma cell disorder and symptom management 3

ATTRwt (Wild-Type)

• Approximately 30% may have polyneuropathy, though it may not be attributable to amyloidosis 1
• Neuropathy is usually milder with less prominent autonomic dysfunction than ATTRv 1
• TTR silencers are not indicated; focus on symptom management 1